In KEYNOTE-522 (NCT03036488), neoadjuvant pembro + chemo significantly increased the pathologic complete response (pCR) rate vs pbo + chemo (64.8% vs 51.2%; P<0.001) in early TNBC. We evaluated outcomes among pts enrolled in Asia.
Pts with previously untreated, nonmetastatic, centrally confirmed TNBC (T1c N1-2 or T2-4 N0-2 per AJCC) were randomized 2:1 to pembro 200 mg Q3W or pbo, both given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant phase). After definitive surgery, pts received pembro/pbo for 9 cycles or until recurrence or unacceptable toxicity (adjuvant phase). Pts were stratified by nodal status (+ vs −), tumor size (T1/T2 vs T3/T4), and carboplatin schedule (Q3W vs QW). Primary endpoints were pCR defined as ypT0/Tis ypN0 and event-free survival. Secondary endpoints included pCR defined as ypT0 ypN0 and ypT0/Tis and OS, and all efficacy outcomes in pts with tumor PD-L1 combined positive score (CPS) ≥1. AEs were monitored until 30 days after treatment discontinuation. No alpha was assigned to this analysis.
As of Sep 24, 2018, 215/1174 pts in the overall population were enrolled from Korea, Japan, Taiwan, and Singapore (pembro, n = 136; pbo, n = 79). Median age was 46 y in the pembro arm and 51 y in the pbo arm. Median follow-up was 13.0 mo. pCR rates (ypT0/Tis ypN0; primary endpoint) among the first 125 randomized pts (pembro, n = 75; pbo, n = 50) were 59% (95% CI, 47–70) with pembro vs 40% (95% CI, 26–55) with pbo (difference, 19%; 95% CI, 1–35). Results were consistent for the secondary pCR definitions, ypT0 ypN0 (51% vs 30%) and ypT0/Tis (61% vs 42%). pCR rates (ypT0/Tis ypN0) were 71% vs 63% in pts with CPS ≥10 and 51% vs 26% with CPS <10. Across both phases for all 215 pts (safety set), incidence of grade ≥3 treatment-related AEs was 75% with pembro vs 76% with pbo (no deaths for either).
Consistent with the overall study population, pembro + neoadjuvant chemo demonstrated clinically meaningful improvement in pCR rates in pts from Asia with early TNBC. AEs were consistent with the known safety profiles of each agent.
NCT03036488.
Medical writing and editorial assistance was provided by Rozena Varghese, PharmD, CMPP, of ICON plc (North Wales, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
R. Dent: Advisory/Consultancy: AstraZeneca; Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Merck; Pfizer; Roche. J. Cortes: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Pfizer; Honoraria (self): Samsung Bioepis; Honoraria (self), Advisory/Consultancy: Celgene; Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharpe & Dohme; Advisory/Consultancy: Cellestia; Biothera Pharmaceuticals; Merus; Seattle Genetics; Erytech; Athenex; Polyphor; Servier; Ariad Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Research grant/Funding (institution): Baxalta GMBH/Servier Affaires; Bayer Healthcare; Piqur Therapeutics; Puma C; Queen Mary University of London; Seagen; Shareholder/Stockholder/Stock options: MedSIR. L. Pusztai: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Genentech; Eisai; Pieris; Immunomedics; Almac; Syndax; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Seattle Genetics. H.L. McArthur: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Bristol-Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses: Spectrum Pharm; Lilly; Amgen; Immunomedics; Pfizer; Genentech; AstraZeneca; Travel/Accommodation/Expenses: Puma Biotechnology. S. Kuemmel: Advisory/Consultancy: Roche; Genomic Health; Novartis; Amgen; Celgene; Daiichi Sankyo; AstraZeneca; Somatex; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Pfizer; PFM Medical; Lilly; Sonoscape; Research grant/Funding (institution): Roche, Somatex; Shareholder/Stockholder/Stock options, Minority Ownership Interest: WSG Study Group; Travel/Accommodation/Expenses: Roche, Daiichi Sankyo, Sonoscape. J. Bergh: Research grant/Funding (institution): Amgen; AstraZeneca; Bayer; Merck; Roche; Pfizer; Sanofi Aventis. C. Denkert: Honoraria (self): Teva; Novartis; Pfizer; Roche; Amgen; Advisory/Consultancy: Amgen; MSD; Daiichi Sankyo; Shareholder/Stockholder/Stock options: Sividon (Myriad); Licensing/Royalties: VmScope. Y.H. Park: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Research grant/Funding (self): Eisai; Advisory/Consultancy, Research grant/Funding (self): Roche; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck; Research grant/Funding (self): AstraZeneca. R. Hui: Honoraria (self), Advisory/Consultancy: MSD; Novartis; Roche; AstraZeneca; BMS; Eli Lilly. N. Harbeck: Advisory/Consultancy: BMS; Roche; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Speaker Bureau/Expert testimony, Fees for Non-CME Services: Roche; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M. Takahashi: Honoraria (self): AstraZeneca; Pfizer; Eli Lilly; Eisai; Research grant/Funding (self): Eisai; Taiho; Kyowa-Hakko Kirin; Nippon Kayaku. T. Foukakis: Honoraria (self), Honoraria (institution), Research grant/Funding (institution): Roche; Honoraria (self), Travel/Accommodation/Expenses: Novartis; Honoraria (institution), Research grant/Funding (institution): Pfizer; Licensing/Royalties: Wolters Kluwer Health. P.A. Fasching: Honoraria (institution): Novartis; Biontech; Cepheid; Honoraria (self): Novartis; Roche; Pfizer; Celgene; Daiichi-Sankyo; Teva; AstraZeneca; Merck Sharp & Dohme; Myelo Therapeutics; MacroGenics; Eisai; Puma; Advisory/Consultancy: Novartis; Roche; Pfizer; Celgene; Daiichi-Sankyo; Teva; AstraZeneca; Merck Sharp & Dohme; Myelo Therapeutics; MacroGenics; Eisai; Puma; Research grant/Funding (institution): Novartis; Biontech; Cepheid. F. Cardoso: Advisory/Consultancy, Research grant/Funding (institution): Amgen; AstraZeneca; Daiichi-Sankyo; Eisai; Genentech; GlaxoSmithKline; MacroGenics; MSD; Novartis; Pfizer; Pierre-Fabre; Roche; Sanofi; Advisory/Consultancy: Astellas/Medivation; Celgene; GE Oncology; Medscape; Merus BV; Mylan; Mundipharma; prIME Oncology; Seattle Genetics; Teva; Research grant/Funding (institution): Boehringer Ingelheim; Bristol-Myers Squibb; Fresenius GmbH; Ipsen; Incyte; Nektar Therapeutics; Nerviano; Medigene; MedImmune; Millenium; Sonus; Tesaro; Tigris; Wilex; Wyeth; Officer/Board of Directors: ESMO Board of Directors. L. Jia; E. Jensen; V. Karantza; G. Aktan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. J. O'Shaughnessy: Honoraria (self): AbbVie Inc; Agendia; Amgen Biotechnology; AstraZeneca; Bristol-Myers Squibb; Celgene Corporation; Eisai; Genentech; Genomic Health; GRAIL; Immunomedics; Heron Therapeutics; Ipsen Biopharmaceuticals; Jounce Therapeutics; Lilly; Merck; Myriad; Novartis; Nov. P. Schmid: Honoraria (self): Pfizer, AZ, Novartis, Roche, Merck, BI, Bayer, Eisai, Puma, Celgene; Advisory/Consultancy: Pfizer, AZ, Novartis, Roche, Merck, BI, Bayer, Eisai, Puma, Celgene; Research grant/Funding (institution): AZ, Genentech, Roche, Oncogenex, Novartis, Astellas; Spouse/Financial dependant, Spouse is a Consultant: Genentech/Roche.
In KEYNOTE-355 (NCT02819518), pembro + chemo significantly improved PFS vs chemo in previously untreated locally recurrent inoperable or metastatic TNBC with tumor PD-L1 combined positive score (CPS) ≥10. We evaluated outcomes among pts in KEYNOTE-355 enrolled at sites in Asia.
Pts with de novo or locally recurrent inoperable/metastatic TNBC with disease-free interval ≥6 mo were randomized 2:1 to pembro vs pbo (up to 35 administrations) + chemo (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) until completion or progression/toxicity. Pts were stratified by chemo (taxane vs gemcitabine/carboplatin), PD-L1 CPS (≥1 vs <1), and prior (neo)adjuvant treatment with same-class chemo (yes vs no). Primary endpoints were PFS (RECIST v1.1 by BICR) and OS in the intent-to-treat (ITT) population (pop) and in PD-L1–positive pts (CPS ≥10 and ≥1). Median PFS was estimated using the Kaplan-Meier method. HRs and 95% CIs were from a Cox regression model. AEs were monitored until 30 d post-treatment (90 d for serious AEs; NCI CTCAE v4.0). No alpha was assigned to this Asian subgroup analysis.
As of Dec 11, 2019, 160 pts were enrolled from Hong Kong, Japan, Korea, Malaysia, and Taiwan (pembro + chemo, n = 113; chemo, n = 47). Median follow-up was 25.7 mo. Pembro + chemo improved PFS vs chemo in the ITT pop; the treatment effect increased with PD-L1 enrichment (Table). Incidence of grade ≥3 treatment-related AEs was 78% with pembro + chemo vs 79% with chemo (no deaths in either group).
Consistent with the overall pop, pembro + chemo showed clinically meaningful improvement in PFS vs chemo in the ITT pop and in PD-L1–positive pts enrolled in Asia with previously untreated locally recurrent inoperable or metastatic TNBC. The benefit was most pronounced in pts with PD-L1 CPS ≥10. Pembro + chemo was tolerable in these pts. C, chemo; P, pembro. *Overall population: P + C (n = 220), C (n = 103). †Overall population: P + C (n = 425), C (n = 211). ‡Overall population: P + C (n = 566), C (n = 281).
Population Treatment Median PFS, mo HR (95% CI) CPS ≥10* P + C (n = 38) 17.3 0.45 (0.22–0.91) C (n = 18) 5.6 CPS ≥1† P + C (n = 81) 7.7 0.56 (0.36–0.89) C (n = 36) 5.6 ITT‡ P + C (n = 113) 8.8 0.61 (0.41–0.90) C (n = 47) 6.7
NCT02819518.
Medical writing and editorial assistance was provided by Rozena Varghese, PharmD, CMPP, of ICON plc (North Wales, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
D.W. Cescon: Honoraria (self): Novartis; Pfizer; Advisory/Consultancy: Agendia; AstraZeneca; Genomic Health; GlaxoSmithKline; Merck; Novartis; Pfizer; Puma Biotechnology; Roche/Genentech; Research grant/Funding (institution): GlaxoSmithKline; Merck; Pfizer; Roche/Genentech; Licensing/Royalties, Patent pending (assigned to institution): Biomarkers of TTK inhibitors. H.S. Rugo: Research grant/Funding (institution), Financial support for clinical trials: Pfizer, Merck, Novartis, Lilly, Genentech, OBI, Odonate, Daiichi, Seattle Genetics, Eisai, Macrogenics, Sermonix, and Immunomedics; Advisory/Consultancy: Puma; Samsung. S-A. Im: Advisory/Consultancy: Amgen; AstraZeneca; Eisai; Hanmi; Lilly; Medpacto, Inc.; Novartis; Pfizer; Roche/Genentech; Research grant/Funding (self): AstraZeneca; Pfizer; Roche/Genentech; Travel/Accommodation/Expenses: Novartis; Roche/Genentech. C. Gallardo: Advisory/Consultancy: Lilly; MSD; Roche; Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Research grant/Funding (self): Novartis Pharma SAS; Roche; Travel/Accommodation/Expenses: MSD; Roche. C.H. Barrios: Advisory/Consultancy: Boehringer Ingelheim; Eisai Europe Ltd.; GlaxoSmithKline; Novartis Pharma SAS; Pfizer Pharmaceuticals Israel; Roche/Genentech; Research grant/Funding (self): AB Science; Abraxis BioScience; Amgen; Asana Biosciences; Astellas Pharma; AstraZeneca; Biomarin; Boehringer Ingelheim; Bristol-Myers Squibb; Daiichi Sankyo; Exelixis; GlaxoSmithKline; ImClone Systems; LEO Pharma; Lilly; Medivation; Merck; Merrimack; Mill; Research grant/Funding (self), Investigator in AbbVie-sponsored clinical trials: AbbVie. H. Iwata: Honoraria (self): AstraZeneca; Chugai Pharma; Daiichi Sankyo; Eisai; Kyowa Hakko Kirin; Lilly Japan; Novartis; Pfizer; Advisory/Consultancy: AstraZeneca; Chugai Pharma; Daiichi Sankyo; Kyowa Hakko Kirin; Lilly Japan; Novartis; Pfizer; Research grant/Funding (institution): AstraZeneca; Bayer; Chugai Pharma; Daiichi Sankyo; Eisai; GlaxoSmithKline; Kyowa Hakko Kirin; Lilly Japan; MSD; Nihonkayaku; Novartis; Pfizer. N. Masuda: Leadership role: Japan Breast Cancer Research Group Association (JBCRG); Honoraria (self): AstraZeneca; Chugai Pharma; Eisai; Lilly Japan; Pfizer; Takeda; Research grant/Funding (institution): AstraZeneca; Chugai Pharma; Daiichi Sankyo; Eisai; Kyowa Hakko Kirin; Lilly; MSD; Novartis; Pfizer. E. Gokmen: Honoraria (self): Eli Lilly; Janssen Oncology; Novartis; Pfizer; Roche; Advisory/Consultancy: Lilly; Novartis; Pfizer; Roche; Speaker Bureau/Expert testimony: Lilly; Novartis; Pfizer; Roche; Travel/Accommodation/Expenses: BMS; MSD Oncology; Novartis; Pfizer; Roche. S. Loi: Advisory/Consultancy: Aduro Biotech; AstraZeneca/MedImmune; Bristol-Myers Squibb; G1 Therapeutics; Merck Sharp & Dohme; Novartis; Pfizer; Roche/Genentech; Seattle Genetics; Research grant/Funding (institution): Bristol-Myers Squibb; Lilly; Merck; Novartis; Puma Biotechnology; Roche/Genentech; Seattle Genetics. Z. Guo: Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.; Shareholder/Stockholder/Stock options: Genmab (I). E. Jensen: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. G. Aktan: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. V. Karantza: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. P. Schmid: Full/Part-time employment: Genentech; Roche; Honoraria (self): AstraZeneca; Novartis; Pfizer; Roche; Advisory/Consultancy: AstraZeneca; Bayer; Boehringer Ingelheim; Celgene; Eisai; Genentech/Roche; Merck; Novartis; Pfizer; Puma Biotechnology; Research grant/Funding (institution): Astellas Pharma; AstraZeneca; Genentech; Novartis; Oncogenex; Roche. J. Cortes: Shareholder/Stockholder/Stock options: MedSIR; Honoraria (self): Celgene; Daiichi Sankyo; Eisai; Lilly; Merck Sharp & Dohme; Novartis; Pfizer; Roche; Samsung; Advisory/Consultancy: AstraZeneca; Athenex; Bioasis; Biothera; Celgene; Cellestia Biotech; Clovis Oncology; Daiichi Sankyo; Erytech Pharma; GlaxoSmithKline; Leuko; Lilly; Merck Sharp & Dohme; Merus; Polyphor; Roche; Seattle Genetics; Servier; Research grant/Funding (institution): ARIAD; AstraZeneca; Baxalta GMBH/Servier Affaires; Bayer; Eisai Farmaceutica; Guardant Health; Merck Sharp & Dohme; Pfizer; Piqur; Puma CO; Queen Mary University of London; Roche; Travel/Accommodation/Expenses: Daiichi Sankyo; Eisai; Novartis; Pfizer; Roche. All other authors have declared no conflicts of interest.
Standard of care for mTNBC is chemo but associated with short duration of response and considerable toxicity. KEYNOTE-119 (NCT02555657) is a randomized, open-label, phase III study of pembro vs chemo as 2nd- or 3rd-line treatment for patients (pts) with mTNBC. Results for the Asia-Pacific (AP) subpopulation are presented.
Pts were ≥18 y with stage IV/M1 TNBC that progressed on or after 1-2 prior treatments, including anthracycline and/or taxane. Pts were stratified by PD-L1 status (positive [combined positive score {CPS} ≥1] vs negative [CPS <1]) and history of (neo)adjuvant treatment vs de novo metastatic disease. Pts were randomly assigned 1:1 to pembro 200 mg IV Q3W or physicians’ choice of single-agent chemo (capecitabine, eribulin, gemcitabine, or vinorelbine). Response assessed by CT/MRI Q9W for first year and Q12W thereafter. Primary end points: OS in pts with PD-L1+ tumors (CPS ≥10, ≥1) and in all pts. Secondary end points: PFS, ORR, and DOR per RECIST v1.1. Exploratory end points: OS, PFS, ORR, and DOR in pts with PD-L1+ tumors (CPS ≥20).
Of 622 pts, 181 were included in the AP group (n=83 pembro; n=98 chemo). Median time from randomization to data cutoff: 31.4 and 32.8 mo in pembro and chemo arms, respectively. Approximately half of pts had PD-L1+ tumors (CPS ≥1, n=103 [57%]; CPS ≥10, n=46 [25%]; CPS ≥20, n=24 [13%]). Median OS with pembro vs chemo was 15.6 vs 17.8 mo in pts with CPS ≥10, 12.2 vs 15.1 mo in pts with CPS ≥1, 11.6 mo vs 13.8 mo in all pts, and 23.5 vs 19.1 mo in pts with CPS ≥20. Median PFS in all pts was 2.1 mo with pembro vs 4.1 mo with chemo. ORR was 12% (n=10) in pembro and 13% (n=13) in chemo; 3 pts in each arm had complete response. Median DOR was 13.4 mo in pembro and 8.4 mo in chemo. Grade 3/4 TRAEs were in 16% and 45% of pts in pembro and chemo arms, respectively. No deaths from TRAEs occurred.
Pembro did not show improved OS vs chemo in the AP subpopulation, but in an ad hoc analysis of pts with CPS ≥20, there was a numeric improvement in OS vs chemotherapy. Additionally, DOR for all pts was numerically higher with pembro vs chemo. Pembro was well tolerated, vs chemo. Results in the AP subpopulation were consistent with the global population.
NCT02555657; September 21, 2015.
Medical writing and/or editorial assistance was provided by Matt Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
S-A. Im: Research grant/Funding (self): AstraZeneca, Novartis, Pfizer, Roche; Travel/Accommodation/Expenses: Amgen, Eisai, Hanmi, Lilly, Novartis, Pfizer, Roche; Advisory/Consultancy: MSD; Leadership role: Dae Woong. J. Cortes: Advisory/Consultancy: Rocher, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Serview, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, boehringer Ingelheim, Kyowa Kirin; Honoraria (self): Roche, Celgene, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Novartis, Eisai, Pfizer, Samsung Bioepis; Research grant/Funding (institution): Roche, AstraZeneca, Merck Sharp & Dohme, Eisai, Pfizer, Ariad Pharmaceuticals, Baxalta GMBH/Serview Affaires, Bayer Healthcare, Guardanth Health, Piqur Therapeutics, Puma C, Queen Mary University of London; Travel/Accommodation/Expenses: Roche, Daiichi Sankyo, Novartis, Eisai, Pfizer; Shareholder/Stockholder/Stock options: MedSIR. A. Goncalves: Non-remunerated activity/ies: Roche, AstraZeneca, Novartis, Pfizer. K-S. Lee: Travel/Accommodation/Expenses: Roche, Lilly, Novartis; Non-remunerated activity/ies: Dong-A Pharm. P. Schmid: Honoraria (self): AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche; Research grant/Funding (institution): AstraZeneca, Novartis, Roche, Astellas, Genentech, Oncogenex. L. Testa: Advisory/Consultancy: MSD, Lily, Novartis, Genomic Health; Non-remunerated activity/ies: Lilly, Novartis, Pfizer, Roche, Libbs; Travel/Accommodation/Expenses: Pfizer, Roche, Libbs, United Medical. I. Witzel: Travel/Accommodation/Expenses: Amgen, Pfizer, Novartis, Roche, MSD. S. Ohtani: Honoraria (institution): Chugai, AstraZeneca, Pfizer, Lilly, Eisai. N. Harbeck: Honoraria (self): BMS, MSD, Roche. F. Andre: Research grant/Funding (self): Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, Lilly. R. Dent: Honoraria (self): AstraZeneca, Merck, Pfizer, Roche, Eisai, Novartis, Lilly; Travel/Accommodation/Expenses: Roche. J. Lin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck. V. Karantza: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck. J.A. Mejia: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck. E.P. Winer: Honoraria (self): Roche, Genentech. All other authors have declared no conflicts of interest.
MONARCH 2 demonstrated that the addition of abemaciclib, an oral CDK4 & 6 inhibitor dosed on a continuous schedule, to fulvestrant (F) significantly improved progression-free survival (PFS) (median 16.4 v 9.3 mo; HR: 0.553; p<.001) and resulted in an overall survival (OS) benefit of 9.4 months compared to placebo (P) plus (+) F (median 46.7 v 37.3 mo; HR: 0.757; p=.01) for patients (pts) with HR+, HER2- advanced breast cancer (ABC) who progressed on endocrine therapy (ET). Consistent with the ITT population and pts from other regions, PFS benefit was previously reported in East Asian pts (Japan, Korea, Taiwan) with a median of 21.2 mo for abemaciclib + F and 11.6 mo for P + F (HR: 0.520; p<.001). The safety profile was manageable. Here we report OS and other updated efficacy and safety data in East Asian pts.
MONARCH 2 was a phase III, global, double-blind, 2:1 randomized trial of abemaciclib + F or P + F in pts (N=669) with HR+, HER2- ABC who progressed on ET. Pre- or perimenopausal (with ovarian suppression) and postmenopausal women received abemaciclib or P (150mg Q12H) and F (500mg per label). Exploratory subgroup analyses were conducted among East Asian pts in the ITT population. HR in East Asian pts was estimated using Cox model, with the log-rank test performed.
In the ITT population, 212 East Asian pts were randomized to abemaciclib + F (n=147) or P + F (n=65). At data cutoff (20June2019), 89 OS events were observed in East Asian pts, with a median OS not reached for abemaciclib + F and 48.9 mo for P + F (HR: 0.798 95% CI 0.515, 1.235; p=.38). The OS rates at 42 mo were 64% (95% CI 55.5, 71.8) for abemaciclib + F and 53% (95% CI 39.9, 64.6) for P + F. PFS2 (HR: 0.588 95% CI 0.420, 0.823; p=.001), time to chemotherapy (HR: 0.601 95% CI 0.411, 0.877; p=.008) and chemotherapy-free survival (HR: 0.573 95% CI 0.402, 0.815; p=.002) were all significantly improved in pts treated with abemaciclib + F. No new safety signals were reported and the safety profile was consistent with previously reported safety data in East Asian pts.
Consistent with previous reports in the ITT population, abemaciclib + F was an effective and tolerable treatment for East Asian patients with HR+, HER2- ABC who progressed on ET.
NCT02107703.
Writing and editorial support provided by Sarah C. Nabinger (Eli Lilly and Company).
Eli Lilly and Company.
Eli Lilly and Company.
C-S. Huang: Advisory/Consultancy, Research grant/Funding (institution), non-financial support: Eli Lilly and Company; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Research grant/Funding (institution), Travel/Accommodation/Expenses, non-financial support: AstraZeneca; Research grant/Funding (institution): EirGenix; OBI Pharma; MSD; Daiichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, non-financial support: Roche. M. Toi: Honoraria (self), Research grant/Funding (institution): Chugai, Takeda, Pfizer; Officer/Board of Directors: Organisation for Oncology and Translational Research; Officer/Board of Directors: Kyoto Breast Cancer Research Network; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), advisory role for drug development: Kyowa-Hakko-Kirin; Honoraria (self), Research grant/Funding (institution): Taiho; Research grant/Funding (institution), Officer/Board of Directors: JBCRG association; Honoraria (self), Research grant/Funding (institution): Eisai; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), advisory role for drug development: Daiichi-Sankyo; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Eli Lilly and Company; Honoraria (self): MSD; Honoraria (self): Genomic Health; Honoraria (self): Novartis; Honoraria (self), Honoraria for advisory meeting: Konica Minolta; Research grant/Funding (institution): Astellas, AFI Technologies; Honoraria (self), Honoraria for advisory meeting: BMS; Honoraria (self), Research grant/Funding (institution): Shimadzu; Honoraria (self): Yakult; Honoraria (self), Research grant/Funding (institution): Nippon Kayaku; Advisory/Consultancy: Athenex Oncology, Bertis. H. Iwata: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly and Company-Japan; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Chugai Pharm; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Daiichi-Sankyo; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Kyowa Hakko Kirin; Honoraria (self), Research grant/Funding (institution): Eisai; Research grant/Funding (institution): GlaxoSmithklin; Research grant/Funding (institution): Nihon Kayaku; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Boehringer Ingelheim. J. Sohn: Research grant/Funding (institution): MSD; Roche; Novartis; AstraZeneca; Eli Lilly and Company; Pfizer; Bayer; GSK; Contessa; Daiichi Sankyo. N. Masuda: Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Eli Lilly and Company; Honoraria (self), Research grant/Funding (institution): Eisai; Honoraria (self), Research grant/Funding (institution): Takeda; Honoraria (self), Research grant/Funding (institution): Kyowa-Kirin; Research grant/Funding (institution): MSD; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Daiichi-Sankyo. S-A. Im: Advisory/Consultancy: Amgen; Hanmi Corp; MSS; Eli Lilly and Company; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Eisai; Pfizer; Roche; Dae-Woong. Y. Lu; N. Haddad; S. Sakaguchi; K. Hurt: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly and Company. P. Neven: Advisory/Consultancy, fees to Institution: Pfizer; Novartis; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, fees to Institution: Eli Lilly and Company; Advisory/Consultancy, fees to Institution: Roche; Research grant/Funding (self): Kom op Tegen Kanker; Research grant/Funding (institution), Institution receives fees for my lecture/attendance at scientific exchange meetings: My Institution. A. Llombart-Cussac: Honoraria (self), Research grant/Funding (institution), personal fees and non-financial support: Novartis; Roche; AstraZeneca; Pfizer; Eli Lilly and Company; Research grant/Funding (institution), non-financial support: Eisai; Honoraria (self), Research grant/Funding (institution), personal fees: Genomichealth; GSK Tesaro; Honoraria (self), personal fees: MSD; Honoraria (self), personal fees and non-financial support: Bristol; Shareholder/Stockholder/Stock options, stock, patents and intellectual property: MedSIR. G. Sledge: Research grant/Funding (institution), Travel/Accommodation/Expenses: Eli Lilly and Company; Officer/Board of Directors: Tessa Therapeutics; Research grant/Funding (institution): Pfizer; Advisory/Consultancy, SAB: Verseau Inc; Advisory/Consultancy, SAB: Syndax. All other authors have declared no conflicts of interest.
Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), has been approved for the indication of HER2+ MBC (N+C) and Early HER2+ BC. In a multinational, randomized, open-label, phase III trial (NALA; NCT01808573), N+C was shown to significantly extend progression free survival (PFS) and time to intervention for central nervous system (CNS) disease vs L+C in HER2+ MBC patients (pts) with ≥2 prior HER2-directed regimens. Here, we present the exploratory pan-Asian subgroup analysis from the NALA study.
Centrally confirmed HER2+ MBC pts were randomized 1:1 to N (240mg qd) + C (750mg/m2 bid, day 1-14) or L (1250mg qd) + C (1000mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally confirmed PFS and overall survival (OS). Secondary endpoints included intervention for CNS disease, objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and safety.
202 Asian pts were enrolled, 63.9% were Chinese from Taiwan and Hong Kong (n=129). In Asian pts, significant improvement in PFS (median 7.0 vs 5.4 mo, HR=0.58; p<0.001) and overall cumulative incidence of intervention for CNS disease (27.9 vs 33.8%; p=0.039) was observed for N+C vs L+C, and a positive trend in OS was noted (median: 23.8 vs 18.7 mo, HR=0.79; p=0.185). Detailed efficacy data are presented in the table. Diarrhea was the most frequent treatment-emergent adverse event for both arms (78.8% vs 51.0%). All events of treatment-emergent diarrhea were ≤ grade 3. Treatment discontinuation rates due to diarrhea were comparable in both arms (N+C vs. L+C 1.0 vs 0.0%).
Endpoints Pan-Asian N+C (n=104) L+C(n=98) HR (95% CI) PFS Median (mo) 7.0 5.4 0.58 (0.41, 0.81) K-M Estimates % (95% CI) 6 mo 53.7 (42.9, 63.3) 33.8 (23.9, 43.8) 12 mo 33.5 (23.4, 43.9) 10.0 (4.4, 18.6) 18 mo 19.9 (11.2, 30.4) 4.0 (0.8, 11.6) OS Median (mo) 23.8 18.7 0.79 (0.56, 1.12) K-M Estimates % (95% CI) 6 mo 91.3 (83.9, 95.4) 88.8 (80.7, 93.6) 12 mo 75.7 (66.2, 82.9) 66.3 (56.1, 74.7) 18 mo 60.0 (49.6, 68.9) 50.5 (39.9, 60.2) 24 mo 47.7 (36.6, 58.1) 38.9 (28.4, 49.3) Overall cumulative incidence of intervention for CNS disease % (95% CI) 27.9 (10.4, 48.7) 33.8 (21.5, 46.5) ORR % (95% CI) 40.7 (29.9, 52.2) 32.1 (22.4, 43.2) CBR % (95% CI) 51.9 (40.5, 63.1) 40.5 (29.9, 51.7) DOR Median (mo) 11.1 4.2 0.26 (0.12, 0.52)
The efficacy of N+C in Asian pts was consistent with that of the overall study population. No new safety signal was noted.
NCT01808573.
Medical writing assistance for this abstract was provided by Yi-Hsuan Chung, MS, of Health Care Asia Co., Ltd and funded by CANbridge Pharma Inc.
Puma Biotechnology Inc.
Puma Biotechnology Inc.
N. Masuda: Honoraria (self), Research grant/Funding (self): Chugai; AstraZeneca; Pfizer; Eli-Lilly; Eisai; Honoraria (self): Takeda; Research grant/Funding (self): Kyowa-Kirin; MSD; Novartis; Nihon-Kayaku; Daiichi Sankyo. A. Kwong: Research grant/Funding (institution): AstraZeneca; Novartis; Roche; GSK; Puma; Pfizer; IceCure; Stryker. Y.S. Yap: Honoraria (self): Novartis; Pfizer; Lilly; Eisai; MSD; AstraZeneca. S. Ow: Honoraria (self): AstraZeneca; Pfizer; Novartis; Eli Lilly. K.S. Lee: Honoraria (self): Articulate Science LLC; Advisory/Consultancy: Roche; Eli Lilly; Novartis. S.B. Kim: Advisory/Consultancy, Research grant/Funding (self): Novartis; Research grant/Funding (self): Sanofi-Aventis; Kyowa-Kirin Inc; DongKook Pharm Co.; Advisory/Consultancy: AstraZeneca; Lilly; Enzychem; Dae Hwa Pharmaceutical Co. Ltd.; ISU Abxis; Daiichi-Sankyo. H.C. Chung: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Lilly; Research grant/Funding (institution): GSK; Advisory/Consultancy, Research grant/Funding (institution): MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck-Serono; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Taiho; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Beigene; Research grant/Funding (institution): Incyte; Advisory/Consultancy: Celltrion; Advisory/Consultancy: Gloria; Advisory/Consultancy: Zymework. K. Keyvanjah; J. Bebchuk: Shareholder/Stockholder/Stock options, Full/Part-time employment: Puma Biotechnology Inc.. M-C.J. Chen: Full/Part-time employment: CANbridge Pharmaceuticals Inc.. All other authors have declared no conflicts of interest.